3ZME

Structure of the p53 core domain mutant Y220C bound to the small molecule PhiKan7242

Summary for 3ZME

• Entry DOI: 10.2210/pdb3zme/pdb
• Descriptor: Cellular tumor antigen p53, ZINC ION, 2-(4-(4-fluorophenyl)-5-(1H-pyrrol-1-yl)-1H-pyrazol-1-yl)-N,N-dimethylethanamine, ... (4 entities in total)
• Functional Keywords: transcription, cell cycle, apoptosis, cancer mutation, protein stabilization
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 49789.16

Authors

Joerger, A.C.,Wilcken, R. (deposition date: 2013-02-07, release date: 2013-05-08, Last modification date: 2024-05-08)

Primary citation

Liu, X.,Wilcken, R.,Joerger, A.C.,Chuckowree, I.S.,Amin, J.,Spencer, J.,Fersht, A.R.
Small molecule induced reactivation of mutant p53 in cancer cells.
Nucleic Acids Res., 41:6034-6044, 2013

PubMed Abstract: The p53 cancer mutant Y220C is an excellent paradigm for rescuing the function of conformationally unstable p53 mutants because it has a unique surface crevice that can be targeted by small-molecule stabilizers. Here, we have identified a compound, PK7088, which is active in vitro: PK7088 bound to the mutant with a dissociation constant of 140 μM and raised its melting temperature, and we have determined the binding mode of a close structural analogue by X-ray crystallography. We showed that PK7088 is biologically active in cancer cells carrying the Y220C mutant by a battery of tests. PK7088 increased the amount of folded mutant protein with wild-type conformation, as monitored by immunofluorescence, and restored its transcriptional functions. It induced p53-Y220C-dependent growth inhibition, cell-cycle arrest and apoptosis. Most notably, PK7088 increased the expression levels of p21 and the proapoptotic NOXA protein. PK7088 worked synergistically with Nutlin-3 on up-regulating p21 expression, whereas Nutlin-3 on its own had no effect, consistent with its mechanism of action. PK7088 also restored non-transcriptional apoptotic functions of p53 by triggering nuclear export of BAX to the mitochondria. We suggest a set of criteria for assigning activation of p53.

PubMed: 23630318
DOI: 10.1093/nar/gkt305

Experimental method

X-RAY DIFFRACTION (1.35 Å)